compound 5 [Zhang et al., 2021]   Click here for help

GtoPdb Ligand ID: 11443

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 5 is a non-covalent SARS-CoV-2 Mpro (3CL-pro) inhibitor with in vitro antiviral activity [1]. It appears to provide synergistic antiviral activity with the viral polymerase inhibitor remdesivir in vitro, in a replicon assay that utilised a non-infectious SARS-CoV-2 clone. Structurally, 5 is a derivative of the anticonvulsant drug perampanel, and was designed to optimise perampanel's weak (IC50100-250 μM) Mpro inhibitory activity. Several nM potency inhibitors were identified in this study (e.g. 21, IC50 18 nM in an enzyme kinetic assay), but they did not deliver antiviral activity in the in vitro assays and/or were cytotoxic. Compound 26 with 1 μM antiviral activity and no cytotoxicity was highlighted as a significant lead structure. The crystal structure of 5 bound to SARS-CoV-2 Mpro has been resolved to 1.8 Å and was submitted to the Protein Data Bank with accession ID 7L11.
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Ligand Activity Visualisation Charts

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 2
Hydrogen bond donors 0
Rotatable bonds 6
Topological polar surface area 67.39
Molecular weight 441.12
XLogP 6.52
No. Lipinski's rules broken 1

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES CCCOc1cc(Cl)cc(c1)c1cc(cn(c1=O)c1cccnc1)c1ccccc1C#N
Isomeric SMILES CCCOc1cc(Cl)cc(c1)c1cc(cn(c1=O)c1cccnc1)c1ccccc1C#N
InChI InChI=1S/C26H20ClN3O2/c1-2-10-32-23-12-19(11-21(27)14-23)25-13-20(24-8-4-3-6-18(24)15-28)17-30(26(25)31)22-7-5-9-29-16-22/h3-9,11-14,16-17H,2,10H2,1H3
InChI Key KFGXONJZGIXSGH-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Zhang C-H, Stone EA, Deshmukh M, Ippolito JA, Ghahremanpour MM, Tirado-Rives J, Spasov KA, Zhang S, Takeo Y, Kudalkar SN et al.. (2021)
Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations.
ACS Central Science,. DOI: 10.1021/acscentsci.1c00039